Medical Essay on Cancer Therapy

The development of cancer therapy has a long history. One of the earliest drugs Accel was for treating herpes encephalitis. Gertrude Elion made G-MP the first anti-leukemia drug, by substituting a sulfur atom for the oxygen atom on a purine molecule. Since then several chemical drugs for the treatment of different types of cancer are developed, and several are practiced in clinical settings, known as chemotherapy. Chemotherapy has several adverse side effects like loss of hair, diarrhea, skin rash among other, simply because the chemicals that are used to kill cancer cells also affect normal cells.

Monoclonal antibodies (McAb) are developed for specific cancer-causing genes to treat that type of cancer. The success of such treatment was found to be marginal. Monoclonal antibodies for particular cancer gene tagged with toxin such as ricin, with the concept that mono antibodies should recognize cancer cells and ricin makes the killing. The development of monoclonal antibodies for specific surface targets on cancer cells have resulted in the exponential growth of targeted therapy for improved efficiency; the FDA has approved this evident since several Monoclonal antibody-based therapies.

Background

Within the past decade, monoclonal antibodies have turned out to be important therapeutic drivers that treat malignant and none malignant diseases. The success of treatments that are immune-based, as well as improved consideration of the function of the immune system in the development of cancer and progression, has laid out an extended development of antibody-based treatment. Most McAbs that are currently being used were initially from murine antibodies that were hybridoma-derived.

The subsequent generation of antibodies was utilized, taking into consideration major stimulation issues of human-anti-mouse antibody reactions as well as the incompetent communication of murine source unvarying place of the antibodies with immune accessory cells of human body. In addition, to reduce immunogenicity, humanized monoclonal antibodies were developed to enhance activity; further, antibodies were conjugated with protein toxins and drugs. However, the problems of immunogenicity, toxicity, specificity are to be eliminated.

Mechanisms of monoclonal antibody activity

Monoclonal antibodies (McAb) are the most constantly evolving class of therapeutic cancer treatment. Monoclonal antibodies target Her-2/neu metaplastic breast cancer, non-Hodgkin's lymphoma (NHL), colorectal cancer, B-cell chronic lymphocytic leukemia, severe myelogenous leukemia, and have received approval from FDA. Potential new antibody therapy targets are such as cellular growth receptors, tumor-based neo-angiogenesis mediators, and host harmful immunoregulatory places which hinder the effectiveness of immune reaction to neoplasia.

Despite the early enthusiasm associated with monoclonal antibodies, clinical results were discouraging and did not succeed in fulfilling the great promise of immunotherapy inherent in the specificity of monoclonal antibodies, which allows their selective binding to tumor cells. For a long period, only one monoclonal antibody, muromonab-CD3 was licensed by the FDA. Several factors that underlie low-therapeutic efficacy observed. The unmodified murine monoclonal antibodies had a short in vivo survival in humans and induced immune responses which ended up neutralizing their therapeutic effects (Scott et al. 3).

Antibody-based Cytotoxicity

Cellular cytotoxicity of the antibody is a known effector of immune mechanism where antigen-specific anti-bodies unswerving immune effector cells of the innate immunity, like natural killer cells and macrophages to the termination of antigen-expressing cell cancers. This property depends on the communication between Fc receptors (FcRs) on immune cell accessory and the Fc part of an antibody.

The FcRs for IgG were recognized more than 40 years ago, with the observation that IgG antibodies could be directly cytophilic for macrophages when presented as opsonized red blood cells. The connecting cross-links FcR on the effector cell, and as a result, the effector cell turns out to be activated such as natural killer (NK) cells are initiated with intentions to terminating cancer cells while at the same time releasing chemokines and cytokines.

The human backbones of IgGI isotype have been seen to mediate Fc domain based functions like antibody-dependent cellular cytotoxicity and complement fixation in an effective manner. As a result, it is a commonly used antibody format among available mAbs for cancer therapy. The therapeutic consequences of other mAbs can be attained through binding to the particular antigen and removal of the natural ligand from binding to its receptors which leads to alteration of the signal.

Immunotoxins

On a recent observation, the therapeutic responses induced by murine antibodies were limited since the agents only recruited human effector elements on a weekly basis which includes those that act through antibody-dependent cellular toxicity and were relatively ineffective as cytocidal agents. Besides these early antibodies were not directed against a vital cell surface target, like a receptor for a growth factor which was required for tumor survival and proliferation. To circumvent these issues humanized and human antibodies were developed.

As a proof of concept, anti-idiotypic antibodies were tested and raised, taking advantage of variously expressed tumor-related antigen. These antigen bodies were designed with intentions of binding specific idiotypes associated with cell-surface membrane immunoglobulins. Monoclonal antibodies that are at present being developed include beneficial alteration that serves the purpose of improving the efficiency of the various potential mechanism of actions (Ploessl, Cady, et al. 418).

The effector cells which may mediate ADCC are like the NK cells, monocyte-macrophages and neutrophils. The Monoclonal Antibodies that mediate ADCC active complement system (Strome, Scott E., Edward A. Sausville, and Dean Mann 1087). The classical activation cascade the complement system, complement-dependent cytotoxicity which involves the direct killing of the tumor cells through the formation of membrane attack complex.

Targets of McAbs

Other than targeting tumor cells themselves, monoclonal antibodies have been used in an alternate strategy to target host tissues or proteins which support tumor expression and growth (Schmidt 170). For instance, a potent inhibitor of neo-vascularization bevacizumab, a humanized antibody directed onto vascular endothelial growth factor in combination with chemotherapy was approved for therapy of patients with metastatic colon cancer (Stern 14). Other than this monoclonal antibody, a receptor Ig fusion protein the VEGF-TRAP has been used in targeting VEGF in the therapy of tumor xenograft models and in patients that have renal cell carcinoma.

The other checkpoint system being targeted for immunomodulation cancer therapy involves the membrane molecule PD-1. PD-1 is an immunoinhibitory molecule which is expressed after the actuation of T-cell. As with CTLA-4 knockout mice, mice deficient in PD-1 manifests autoimmune disease. The growth of melanoma cell expressing PDL-1 in usual syngeneic mice was significantly inhibited, although transiently through the management of anti-PDL-1 antibodies (Ma, Weijie, et al. 16).

Furthermore, the growth of tumor was absent in syngeneic PDL molecules on tumor cells can hand out as a mechanism for an otherwise immunogenic tumor to space form host immune response. Therefore, targeting of the interaction of PD-1 with its PDL ligands using monoclonal antibodies may represent a promising strategy to remove this immunological checkpoint and hence argument specific tumor immunity.

Radioimmunotherapy

For radioimmunotherapy, the main issue involves having to balance the dose delivered to a tumour against the exposure of normal organs and tissues to radiation. Two radiolabeled McAbs have been currently licensed. These are ibritumomab tiuxetan and tositumomab, that are McAb conjugated to the b-particle which emits radioisotopes yttrium-90 and iodine-131, in that order. These radioimmunoconjugates used in the therapy of non-Hodkin's lymphoma (NHL) are directed to the CD20 antigen (Fleurence 9). For patients who have solid tumors, the rates of responses to radioimmunotherapy agents are modest.

Generally, after intravenous injection, McAbs accumulate in solid tumors relatively slowly and less than one percent of the dose injected is typically localized per gram of a tumour. Such inefficient accumulation has been attributed to with the help of several physiological barriers between the circulation of blood and tumor-cell surfaces. These barriers are such as size-dependent diffusion properties of antibodies, vascular endothelium, long transport distances in the tumor tissues.

Drug-conjugated monoclonal antibodies

For drug-conjugated monoclonal antibodies, Gemtuzumab ozogamicin is FDA approved for application in relapsed acute myeloid leukemia. This is a humanized antibody that is focused on the MUC1 antigen connecting calicheamicin, an antibiotic which cleaves DNA. The specificity of this particular toxic anti-tumor compound is assured through the recognition of CD33 antigen on the cell surface with the help of internalization of conjugated McAb; the calicheamicin parts can exert the tumor effects selectively (Migliore et al., 645). Studies that involve doxorubicin as the payload drug have been reported as well. Both labeled and unlabeled McAb have been utilized in transplant environment. Particularly, Rituximab has been incorporated into bone-marrow transplant in several forms, with the intentions of exploiting the synergism between chemotherapy and rituximab (Aixinjueluo, Wei, et al.).

Anti-EGFR monoclonal antibodies

Different methods have been proposed that can help in eliciting anti-EGFR mAbs can help in eliciting anti-tumor response including;

EGFR binding on the cell surface that trigger receptor internalization as well as degradation through lysosomal pathways, which prevents the nuclear translocation of DNA-PK hence inhibiting DNA break repair induced through radiation and DNA-avid chemotherapeutic agents (Ferris, Robert L., Elizabeth M. Jaffee, and Soldano Ferrone 4392).

EGFR interface with signaling through prevention of ligand binding as well as unfolding of the tethered EGFR to the extended, more active conformation. This is a possible scenario with domain III, which targets anti-EGFR antibodies like cetuximab, matuzumab or panitumumab.

ADCC

The other mechanism which is not properly understood invokes a broad intervention with events that send signals through disruption antibody of lipid rafts. The EFGR has intimate connections with signaling micro platforms on cellular membrane. Increased concentration of EGFR ligands or maybe, cross-connections with antibody requires internalization of shuttle EGFR from clathrin mediation pathway for recycling to the associated route that leads to receptor degradation.

Conclusion

In sum, Antibodies have been developed as essential therapeutic vehicles for different cancers. Even so, future investigations are likely to define more therapeutic targets and will help in exploring various anti-tumor mechanism. These efforts will gain further abetment through advances made in the engineering of antibodies. While almost every approved antibody requires the presence of the antibody target on the cell surface, within the tumor stroma or the circulating blood, there is a possibility that continued research in this specific area of immunotoxins will result in life-changing directio...